Inflammation in post-traumatic osteoarthritis - The role of proinflammatory cells and cytokines in the DMM model of post-traumatic OA in mice
Final Report Abstract
There is emerging evidence that synovitis in OA may not just result from, but also play an active role in disease initiation and progression. The specific inflammatory events that occur in OA, how these change with time and if they differ from “non-OA-inducing” joint inflammation have yet to be elucidated. A model of surgically induced OA in mice was used to define the temporal influx of inflammatory cells in the synovium and its relationship with the onset and progression of disease. Destabilization of the medial meniscus (DMM) was performed in one knee and sham surgery in the other of ten-week-old male C57BL6 mice. Age- and sex-matched mice were used as non-operated control (NOC). At sacrifice (day 1 to 112 post-surgery) blood, spleen and knee joint synovial membrane (SM) were harvested. Mononuclear cells in the SM (SMMCs), blood (PBMCs) and spleen (SpMCs) were isolated and quantified by FACS, and cytokine expression was measured by qRT-PCR in replicate SM. There was no OA pathology in NOC or sham. OA pathology progressed over 16wk in DMM following initial detection of cartilage erosion at 28-35d, osteophytes at 14d, and subchondral bone sclerosis at 14d. There was no change in PBMC or SpMC any time following surgery. As there was no change in SMMC over time in NOC, a mean ± SD value was used for comparison with sham and DMM. We found 4 distinct peaks in SM cell number after surgery (day 1, 14, 35, 70), each followed by a resolution phase. Cell numbers returned to NOC levels in sham by 21 days, but remained elevated in DMM to day 42. The activated macrophage % rapidly increased but returned to NOC levels by day 35 in both sham and DMM (Fig 1B), although total macrophage numbers remained elevated in DMM. The most striking difference between sham and DMM was in T-cells. At 14 days after surgery there was a transient peak in CD4 and CD8 cells in DMM only. The second T- cells peak (day 28-35) was larger and more sustained in DMM, and from day 56 onwards T-cells, particularly CD4, were only increased in DMM. Quantitative RT-PCR for F4/80, CD4, CD8 mirrored the temporal pattern seen with FACS. Synovial IL-1β and TNF mRNA increased rapidly (day 1) to the same extent after sham and DMM, and returned to NOC levels by 14 days in both groups. We have established distinct phases of synovial inflammation after joint trauma and that these differ with the onset and progression of OA. Differences between sham and DMM were not just numerical, but in the % of different cell types in the inflammatory response. Increased joint macrophages, CD4 and CD8 T-cells with no systemic change (PBMC, SMC) are consistent with established human OA. The DMM model has enabled us to define changes in T-cells that precede overt cartilage erosion and differentiate between OA-inducing and non-inducing joint trauma. This new data supports the hypothesis that synovial T-cells may play a critical role in the development of post-traumatic OA, and that their depletion may provide a novel therapeutic approach.
Publications
- Presence and activity of synovial inflammatory cells in osteoarthritis. 2011 MBANZ Matrix Biology Conference Sydney Australia
Moradi B, Rosshirt N, Jackson MT, Hagmann S, Kretzer JP, Russell AK, Lorenz HM, Zeifang F, TretterT, Little CB
- Post-traumatic osteoarthritis is accompanied by a distinct pattern of synovial inflammatory cell infiltration. Osteoarthritis and Cartilage Volume 20, Supplement 1, Pages S232-S233, April 2012
Moradi B, Jackson MT, Russell AK, Smith SM, Smith MM, Little CB
- Osteoarthritis progression is accompanied by inflammatory CD4+ T-cell polarisation. Osteoarthritis and Cartilage Volume 21, Supplement 1, Pages S60-S61, April 2013
Moradi B, Rosshirt N, Hagmann S, Schnatzer P, Gotterbarm T, Lorenz HM, TretterT, Zeifang F
